Current Topics in Medicinal Chemistry - Volume 17, Issue 22, 2017

For successful drug discovery it is important to understand the fundamentals of the underlying causes and consequences of the diseases for which the drug is being developed. One such physiological process in eukaryotic cells is protein phosphorylation, which is the main post-translational modification of proteins responsible for the onset or progression of Alzheimer's disease, diabetes and various cancers. Protein phosphorylation is facilitated by kinases and inhibitors of kinases act as drugs in controlling or curing these diseases by reducing protein phosphorylation. This review discusses the technologies capable of detecting kinase activity and screening candidate compounds to identify novel inhibitors of protein kinases.

Role of kinase inhibitors in various diseases is well established and discovery of imatinib opens up new paradigms in kinase inhibition. Furthermore, presence of heterocyclic moiety in a kinase inhibitor seems to be essential now. However, the potential of a single heterocyclic moiety was discussed in variety of reviews but a focus review considering the potential of different heterocyclic moieties is unavailable. Based on this, we classify prospective kinase inhibitors on the basis of number of heterocyclic moieties present and summarize the prospective kinase inhibitors. Finally, important key points, current challenges and future prospects of kinase inhibitors are also discussed.

In recent years, several scientific investigations have reported the therapeutic implications of superoxide dismutase (SOD) against oxidative stress and -induced pathology in clinical and preclinical trials. Indeed, various kinase, molecular signaling and physiological process has altered by reactive oxygen species. In spite of the abundant available literature reports, patents, clinical trials and commercialized products, the therapeutic application of SOD as a potential drug still remains unclear. Owing to the technical challenges associated with the utilization of SOD as a drug, we revisited the structural arrangement and cellular signaling, significant association with kinase, exploring the new target sites and introducing new formulation strategies such as gene modulation, nano-formulations and click chemistry is a prerequisite. In-addition to gene modulation strategies, encapsulated formulation within a nano-carrier for producing promising SOD therapeutic effects, application of click chemistry including bioconjugation and cyclo-addition are the most prominent methods to produce highly efficient SOD formulations. Thus, the present review enlightens the foremost technique which may have better interaction with kinase and other cellular signaling for regulating the physiological process.

Mutations in the kinase domain encoding region of EGFR gene causes drug resistance to EGFR kinase inhibitors such as erlotinib and gefitinib. This problem can be addressed by a new lead compound effective against all mutants of EGFR. To predict positions of residues possessing the potential to render EGFR drug resistant upon mutation, residual positions known to interact with Erlotinib and Gefitinib were assessed using five parameters (conservation index, binding site RMSD, protein structure stability and change in ATP and drug binding affinity). Structural screening protocol was followed to identify novel lead compound. Four positions, Lys 745, Cys 797, Asp 800 and Thr 854, were most likely observed to acquire drug resistance by altering drug binding affinity without destabilizing the protein and ATP binding ability. A compound DHO was observed to possess better binding affinity for all EGFR models in comparison to Erlotinib and Gefitinib, using docking protocol. This information would pave the way for designing drugs effective against wild-type (WT) EGFR as well as against variant EGFRs models. Thus, authors report a lead compound as a long-term potential with the ability to inhibit predicted models of mutant, wild and known SNPs EGFR.

Microtubules form crucial dynamic structural cellular components of the cell and are composed of the alpha beta tubulin heterodimers. Microtubules are involved in a wide variety of functions in the cell such as attribution to cell shape, motility, intracellular trafficking and mitotic spindle formation. Owing to these reasons, tubulin and microtubules have gained significant interest as important targets for cancer therapy. A review of the existing microtubule targeting drugs specifies that these agents can be categorised into two of the major categories: Microtubule stabilizing agents such as paclitaxel, docetaxel, epothilones, and discodermolide which bind to the tubulin polymer and stabilize the microtubules, microtubule destabilizing agents such as vinca alkaloids, colchicine and combretastatins which bind to tubulin dimers and cause destabilization. These agents ultimately alter the equilibrium between tubulin and microtubule resulting in disruption of mitotic spindle, thereby effecting a critical transition in the cell cycle, leading to cell death. Further, clinical studies of these agents are limited by toxicity effects and emergence of drug resistance. The hybrid drugs are a combination of two or more drugs wherein pharmacophores are incorporated into a single molecule to interact with multiple targets and enhance the cytotoxic action with minimal side effects. Such hybrid regimens can improve therapeutic efficacy and reduce drug toxicity. Therefore, studies on new hybrids with such biological properties form important part in chemistry. In this review, we present an overview of various recent hybrids of colchicines, combretastatin, phodophyllotoxin, etc generated by combination among themselves through linkers or with other pharmacophores and their properties like tubulin stabilization and tubulin destabilization. We also attempted to provide chemistry, toxicity, resistance, side effects of these molecular hybrids acting as microtubule targeting drugs.

In this paper we provide an overview of the status of various colchicine derivatives in preclinical development with special focus on their anti-cancer activity. We discuss several groups of compounds that have been designed to differentially bind with specific affinities for tubulin β isotypes, especially in regard to βIII, which is commonly over-expressed in cancer. Computational prediction, protein-based and cell-based assays are summarized as well as some animal tests conducted on these compounds. It is concluded that an untapped potential exists for exploiting the colchicine scaffold as a pharmacophore with the possibility of increasing its affinity for tubulin isotypes overexpressed in cancer and decreasing it for normal cells thereby widening the therapeutic window.

Microtubule-targeted drugs (MTDs) have been on the forefront of breast cancer chemotherapy. Classic MTDs, such as paclitaxel and their semisynthetic derivatives, have achieved considerable success in the clinical management of breast neoplasms. In order to improve the specificity and to reduce undesirable, dose-limiting toxicities of these drugs, a plethora of novel compounds are being synthesized and investigated in laboratories worldwide. Due to their crucial roles during cell division, and to the fact that the suppression of their innate ‘dynamic instability’ can arrest cell cycle progression, microtubules formed an attractive target for cancer chemotherapy. Kadcyla (ado-trastuzumab emtansine), Halaven (eribulin mesylate), and Ixempra (Ixabepilone) are three relatively-novel, microtubule-targeting antibreast cancer drugs. Kadcyla was developed by conjugating a very potent derivative of the natural product maytansine to trastuzumab, a HER2-targeted monoclonal antibody. Kadcyla is a double-edged weapon, that is, it prevents receptor dimerization to inhibit cell proliferation, and then it enters inside the target tumour cell by receptor-mediated endocytosis and ensures death of the cell. Halaven (eribulin mesylate), created by simplifying the structure of the marine sponge-derived molecule Halichondrin B, works primarily by suppressing the growth rates of microtubules and thereby inducing cell cycle arrest and cell death. Ixabepilone, the semisynthetic analogue of epothilone B, suppresses the shortening rates of dynamic microtubules resulting in cell cycle inhibition and cell death. In order to improve the efficacy and reduce drug-induced side effects, novel therapeutic strategies, including liposome-mediated drug delivery, are being investigated.

We have recently reported the synthesis and antiproliferative potential of a series of biaryl type α-noscapine congeners. Among them, 9-(3-pyridyl) noscapine 3f (9-PyNos, henceforth), which was synthesized by adding pyridine unit to the tetrahydroisoquinoline part of natural α-noscapine core, was found to be the most effective one to inhibit proliferation of a variety of cancer cell lines. However, details of its interactions with its cellular target, tubulin, remain poorly understood. In this report, we examined the nature of interactions of 9-PyNos with tubulin based on the methodologies of spectrofluorimetry, circular dichroism, and turbidimetry techniques. Far-UV circular dichroism spectra indicated perturbation of tubulin secondary structure in the presence of 9-PyNos, not amounting, however, to the perturbation induced by noscapine. The noscapinoid nevertheless altered the surface configuration of the protein considerably, as indicated by an anilinonaphthalene sulphonate binding assay, and promoted colchicine binding to tubulin, the latter indicating its adjacent binding site with colchicine. 9-PyNos however, did not alter microtubule assembly considerably. Investigating the possible reason behind this apparent lack of strong inhibition of microtubule assembly, we found that the binding interactions of tubulin with 9-PyNos do not involve modification of cysteine residues of tubulin. Taken together, our data suggest that the antiproliferative mechanism of action of 9-PyNos involves disruption of structural integrity of tubulin without strong inhibition of tubulin assembly.